The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDs-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes.
Currently available chemotherapy targets two crucial viral enzymes: HIV protease and HIV reverse transcriptase. (J. S. G. Montaner et al. Antiretroviral therapy: “The State of the Art”, Biomed. & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Highly active antiretroviral therapy(HAART) for the treatment of infection with human immunodeficiency virus type 1, Biomed & Pharmacother. 1999 53:73-86; E. De Clercq, New Developments in Anti-HIV Chemotherap. Curr. Med. Chem. 2001 8:1543-1572). Two general classes of reverse transcriptase inhibitors (RTIs) have been identified: nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs typically are 2′,3′-dideoxynucleoside (ddN) analogs that must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA).
NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity. (R. W. Buckheit, Jr., Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection, Antiviral Res. 1998 38:153-179; G. Moyle, The Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors in Antiviral Therapy, Drugs 2001 61(1):19-26) Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine. Although initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HIV strains when used in monotherapy as well as having and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT.
While combination therapy with NRTIs, PIs and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly reproducing HIV virus has proven adroit at creating mutant drug-resistant variants of wild-type protease and reverse transcriptase.
There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV.
WO 02/100852 (B. W. Dymock et al.) discloses novel pyrazole derivatives, processes for preparing the novel pyrazoles, pharmaceutical compositions containing the pyrazoles and the use of pyrazoles as inhibitors of human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication. WO 02/30907 (B. W. Dymock et al.) also teaches novel pyrazoles useful for inhibiting HIV reverse transcriptase. These patents are hereby incorporated by reference in their entirety.
U.S. Pat. No. 6,005,109 (W. S. Faraci) EP 0 691 128 (G. M. Bright et al.) and EP 0 959 074 (G. M. Bright et al.) disclose pyrazole derivatives which have corticotropin releasing factor antagonist activity.
EP 1 072 597 (Banks, B. J. et al.) disclose pyrazole derivatives with endothelin antagonist activity. WO 97/04773 (J. I. Luengo et al.) discloses phenyl pyrazoles as endothelin receptor antagonists for treating cardiovascular or renal disease.
WO 02/04424 (R. G. Corbau et al.) discloses the use of pyrazole derivatives in the manufacture of reverse transcriptase inhibitor or modulator, to novel pyrazole derivatives and to processes for the preparation pyrazole derivatives and for compositions containing novel pyrazole derivatives. WO 02/085860 (L. H. Jones, et al) disclose pyrazole compounds, processes for the preparation of the pyrazole compounds and uses for the compounds to inhibit or modulate viral enzyme reverse transcriptase. The use of the pyrazoles for the treatment diseases caused Human Immuno-deficiency Virus (HIV) also is taught.
WO 00/66562 (V. B. Lohray et al.) disclose phenylsulfinyl-, phenylsulfonyl- and phenylthio-substituted pyrazole compounds which inhibit r-hu COX-2 useful for inhibiting prostaglandin biosynthesis, and treating pain fever and inflammation. WO 01/16138 (T. Kolasta and M. V. Patel) and WO 01/64669 (H. Cheng et al.) also disclose sulfonylphenyl substituted pyrazole compounds which inhibit COX-2.
Hydroxypyrazole derivatives have been disclosed to have agrochemical pesticide activity. WO 99/33813 (P. Desbordes et al.) discloses fungicidal aryloxypyrazoles.